Expanding the Arsenal of Pt^IV Anticancer Agents: Multi-action Pt^IV Anticancer Agents with Bioactive Ligands Possessing a Hydroxy Functional Group

Most multi-action Pt^IV prodrugs have bioactive ligands containing carboxylates. This is probably due to the ease of carboxylating the OH axial ligands and because following reduction, the active drug is released. A major challenge is to expand the arsenal of bioactive ligands to include those without carboxylates. We describe a general approach for synthesis of Pt^IV prodrugs that release drugs with OH groups. We linked the OH groups of gemcitabine (Gem), paclitaxel (Tax), and estramustine (EM) to the Pt^IV derivative of cisplatin by a carbonate bridge. Following reduction, the axial ligands lost CO₂, rapidly generating the active drugs. In contrast, succinate-linked drugs did not readily release the free drugs. The carbonate-bridged ctc-[Pt(NH₃)₂(PhB)(Gem-Carb)Cl₂] was significantly more cytotoxic than the succinate-bridged ctc-[Pt(NH₃)₂(PhB)(Gem-Suc)Cl₂], and more potent and less toxic than gemcitabine, cisplatin, and co-administration of cisplatin and gemcitabine.